TW201609699A - Compounds with ALK inhibitory activities, process for preparing and their use thereof - Google Patents

Compounds with ALK inhibitory activities, process for preparing and their use thereof Download PDF

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TW201609699A
TW201609699A TW103141352A TW103141352A TW201609699A TW 201609699 A TW201609699 A TW 201609699A TW 103141352 A TW103141352 A TW 103141352A TW 103141352 A TW103141352 A TW 103141352A TW 201609699 A TW201609699 A TW 201609699A
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compound
alkyl
cycloalkyl
halogen
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仝朝龍
孫興義
盛錫軍
張秀春
喻紅平
徐耀昌
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上海翰森生物醫藥科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

This invention relates to compounds as general formula (I) or its pharmaceutical salts, especially relates to compounds as general formula (I) or its pharmaceutical salts, process for preparing and their use thereof, the compounds have activity in ALK inhibition, they can be used to treat cancers which show positive in ALK, they have broad prospect in pharmaceutical use.

Description

具有ALK抑制活性的化合物及其製備與用途 Compound with ALK inhibitory activity and preparation and use thereof

本發明屬於藥物化學技術領域，具體涉及具有ALK抑制活性的化合物及其製備與用途。 The invention belongs to the technical field of medicinal chemistry, and particularly relates to a compound having ALK inhibitory activity and preparation and use thereof.

間變性淋巴瘤激酶(ALK)是一種受體酪胺酸蛋白激酶，最早是在間變性大細胞淋巴瘤(ALCL)的一個亞型中被發現的，因此定名為間變性淋巴瘤激酶(anaplastic lymphoma kinase，ALK)(Morris,S.W.等，Science,1994,263,1281-1284；Shiota,M.等，Oncogene,1994,9,1567-1574)。ALK蛋白含有1620個胺基酸，分子量為177千道爾頓(kDa)，254個胺基酸激酶結構域由1123至1376位胺基酸殘基組成，在此之前是一個由胺基酸組成的短跨膜區。在小鼠體內的表達形式提示其在中樞和外周神經系統的發育中起作用；在果蠅中發現ALK以配體結合的形式促進腸管肌肉組織形成，哺乳動物配體尚未確定；人類視網膜中檢測到ALK蛋白質。ALK基因剔除的小鼠生命週期和生命活動未見明顯異常(Webb,T.R.等，Expert Rev.Anti-cancer Ther.,2009,9,331-356)，預示著ALK抑制將不會對有機體 造成嚴重的傷害。 Anaplastic lymphoma kinase (ALK) is a receptor tyrosine protein kinase that was first discovered in a subtype of anaplastic large cell lymphoma (ALCL) and was therefore named anaplastic lymphoma. Kinase, ALK) (Morris, SW et al, Science, 1994, 263, 1281-1284; Shiota, M. et al, Oncogene, 1994, 9, 1567-1574). The ALK protein contains 1620 amino acids with a molecular weight of 177 kilodaltons (kDa) and 254 amino acid kinase domains consisting of amino acid residues 1123 to 1376, which was previously composed of an amino acid. Short transmembrane zone. Expression patterns in mice suggest that it plays a role in the development of the central and peripheral nervous systems; ALK is found in Drosophila to promote intestinal muscle tissue formation in the form of ligand binding, mammalian ligands have not been determined; detection in human retina To the ALK protein. There was no significant abnormality in the life cycle and life activities of ALK knockout mice (Webb, T.R. et al., Expert Rev. Anti-cancer Ther., 2009, 9, 331-356), indicating that ALK inhibition would not be against organisms. Cause serious damage.

2007年兩個獨立研究小組在非小細胞肺癌中分別鑒定出ALK基因重排。其中一組研究人員開發了逆轉錄病毒cDNA表達庫用於篩選新癌基因。他們轉染了提取自一位人員預先篩選顯示KRAS和EGFR突變陰性的62歲日本男性吸煙者肺腺癌的cDNA資料庫，並設計生成了基因轉殖小鼠，在肺泡細胞中特異性表達EML4-ALK，由此生成了許多肺腺癌結節。使用ALK抑制劑治療這些基因轉殖小鼠導致腫瘤負荷相比於未治療的小鼠減小。大部分小鼠很快在1個月內死亡。使用相同ALK抑制劑治療導致肺臟無EML4-ALK/3T3細胞浸潤且生存期延長。此研究有力證實了EML4-ALK是非小細胞肺癌中唯一的驅動突變，並且在體內抑制EML4-ALK活性會導致肺癌負荷減少(Soda,M.,Choi,Y.L.,Enomoto,M.，等，Nature,2007：448)。EML4-ALK融合出現在大約3-5%的非小細胞肺癌中，具體因研究的人群和使用的ALK檢測方法的不同而有所差別，是非小細胞肺癌中的唯一驅動突變基因。 In 2007, two independent research groups identified ALK gene rearrangements in non-small cell lung cancer. One group of researchers developed a retroviral cDNA expression library for screening new oncogenes. They transfected a cDNA library of lung adenocarcinomas from a 62-year-old Japanese male smoker who was pre-screened to show KRAS and EGFR mutations, and designed a gene-transferred mouse to specifically express EML4 in alveolar cells. -ALK, which produces many lung adenocarcinoma nodules. Treatment of these gene-transferred mice with ALK inhibitors resulted in a reduction in tumor burden compared to untreated mice. Most mice die very quickly within 1 month. Treatment with the same ALK inhibitor resulted in no EML4-ALK/3T3 cell infiltration in the lung and prolonged survival. This study strongly confirms that EML4-ALK is the only driving mutation in non-small cell lung cancer, and that inhibition of EML4-ALK activity in vivo leads to a reduction in lung cancer burden (Soda, M., Choi, YL, Enomoto, M., et al., Nature, 2007: 448). EML4-ALK fusion occurs in approximately 3-5% of non-small cell lung cancers, differing between the study population and the ALK assay used, and is the only driver mutation in non-small cell lung cancer.

實驗資料表明，抑制ALK基因可以有效阻止ALK呈陽性的淋巴瘤細胞和肺癌細胞的生長，顯示出ALK抑制劑在這類腫瘤治療中具有重要價值(Piva,R.等，Blood,2006,107,689-697；Galkin,A.V.等，Proc.Natl.Acad.Sci.USA,2007,104,270-275；Koivunen,J.P.等，Clin.Cancer Res.,2008,14,4275-4238)。 Experimental data show that inhibition of ALK gene can effectively prevent the growth of ALK-positive lymphoma cells and lung cancer cells, indicating that ALK inhibitors are of great value in the treatment of such tumors (Piva, R. et al, Blood, 2006, 107, 689- 697; Galkin, AV, et al, Proc. Natl. Acad. Sci. USA, 2007, 104, 270-275; Koivunen, JP et al, Clin. Cancer Res., 2008, 14, 4275-4238).

發明人在研究過程中，發現一類如通式(I)所示的化合物或其可藥用鹽，該化合物具有ALK抑制活性，可用於治療ALK呈陽性的相關癌症，具有廣闊的用藥前景。 During the course of the research, the inventors have found a class of compounds represented by the formula (I) or a pharmaceutically acceptable salt thereof, which has ALK inhibitory activity and can be used for treating cancers which are positive for ALK, and has broad application prospects.

本發明一方面提供一種具有通式(I)的化合物或其可藥用鹽： 其中：環A選自5-10員環烷基、5-10員雜環基、5-10員芳基或5-10員雜芳基；R1選自C1-6烷基、鹵素取代的C1-6烷基、C3-6環烷基或4-甲苯基；R2、R3、R4、R5各自獨立的選自氫、鹵素、羥基、氰基、硝基、C1-6烷基、鹵素取代的C1-6烷基、C3-8環烷基、C1-6烷氧基、鹵素取代的C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11；R6、R7、R8各自獨立的選自氫、鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11， 其中該C1-8烷基、C3-8環烷基、3-8員雜環基、C5-10芳基或5-10員雜芳基各自獨立視需要進一步被一個或多個選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代；R9、R10、R11選自氫、C1-4烷基；m、n為0、1、2、3、4；L為0、1、2、3、4、5；p為0、1或2。 In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein: Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aryl or 5-10 membered heteroaryl; R 1 is selected from C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-6 cycloalkyl or 4-tolyl; R 2 , R 3 , R 4 , R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, C 3-8 cycloalkyl Oxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ; each of R 6 , R 7 , R 8 Independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 Heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O R 9 , —C(O)OR 9 , —NR 10 R 11 or —C(O)NR 11 , wherein the C 1-8 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocyclic group , C 5-10 aryl or 5-10 membered heteroaryl each independently further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 olefin group, C 2-8 alkynyl, C 3-8 cycloalkyl Groups, 3-8 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S (O) pR 9 Substituted with a substituent of -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ; R 9 , R 10 , R 11 are selected from hydrogen, C 1 -4 alkyl; m, n are 0, 1, 2, 3, 4; L is 0, 1, 2, 3, 4, 5; p is 0, 1 or 2.

較佳的，環A與其取代基共同形成的結構選自如下結構： Preferably, the structure formed by ring A together with its substituent is selected from the following structures:

更較佳的，環A與其取代基共同形成的結構選自如下結構： 其中，R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、m、n、 L、p如式(I)化合物所定義。 More preferably, the structure formed by ring A together with its substituent is selected from the following structures: Wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined for the compound of formula (I).

進一步較佳的，R2、R5各自獨立的選自氫、鹵素、C1-6烷基、鹵素取代的C1-6烷基；R3、R4各自獨立的選自氫、鹵素、羥基、氰基、硝基、C1-6烷基、鹵素取代的C1-6烷基、C3-8環烷基、C1-6烷氧基、鹵素取代的C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11；R6、R7、R8、R9、R10、R11、m、n、L、p如式(I)化合物所定義。 Further preferably, R 2 and R 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, halogen-substituted C 1-6 alkyl; and R 3 and R 4 are each independently selected from the group consisting of hydrogen and halogen. Hydroxy, cyano, nitro, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy a group, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined for the compound of formula (I).

最較佳的，該式(I)化合物或其可藥用鹽選自： Most preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

更較佳的，該化合物或其可藥用鹽選自式(II)化合物： 其中：R3選自氫、羥基、氰基、硝基、C3-8環烷基、C1-6烷氧基、鹵素取代的C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11；R2、R4、R5、R6、R7、R8、R9、R10、R11、m、n、L、p如式(I)化合物所定義。 More preferably, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (II): Wherein: R 3 is selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 3-8 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, C 3-8 cycloalkyl Oxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ; R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined for the compound of formula (I).

進一步較佳的，R3選自鹵素取代的C1-6烷氧基；R2、R4、R5、R6、R7、R8、R9、R10、R11、m、n、L、p如式(I)化合物所定義。 Further preferably, R 3 is selected from halogen-substituted C 1-6 alkoxy; R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n , L, p are as defined for the compound of formula (I).

最較佳的，其選自如下化合物： Most preferably, it is selected from the group consisting of:

本發明另一方面提供一種具有通式(I)的化合物的製備方法，該製備方法包括如下步驟：式(III)化合物與式(IV)縮合得到式(I)化合物，或者式(III)化合物與式(IV)縮合，然後根據取代基的不同定義或脫保護基轉換成相應的式(I)化合物，其合成路線如下： 其中，環A、R1、R2、R4、R5、R6、R7、R8、R9、R10、R11、m、n、L、p如式(I)化合物所定義。 According to another aspect of the present invention, there is provided a process for the preparation of a compound of the formula (I), which comprises the step of condensing a compound of the formula (III) with a compound of the formula (IV) to give a compound of the formula (I) or a compound of the formula (III) Condensation with formula (IV), and then conversion to the corresponding compound of formula (I) according to different definitions of the substituent or deprotection group, the synthesis route is as follows: Wherein ring A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined for the compound of formula (I) .

本發明又一方面提供一種藥物組成物，該藥物組成物含有治療有效劑量的前述化合物或其可藥用鹽以及可藥用的載體或賦形劑。 A further aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the foregoing, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

本發明又一方面提供一種調節蛋白激酶催化活性的方法，其包括將該蛋白激酶與前述化合物或其可藥用鹽，或前述藥物組成物相接觸，該蛋白激酶選自間變 性淋巴瘤激酶。 A further aspect of the invention provides a method of modulating catalytic activity of a protein kinase comprising contacting the protein kinase with a compound of the foregoing, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from the group consisting of Lymphoma kinase.

本發明又一方面提供一種前述化合物或其可藥用鹽，或前述藥物組成物在製備治療癌症的藥物中的應用，其中該癌症較佳非小細胞肺癌。 A further aspect of the present invention provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or the use of the aforementioned pharmaceutical composition for the preparation of a medicament for treating cancer, wherein the cancer is preferably non-small cell lung cancer.

詳細說明：除非有相反陳述，下列用在說明書和申請專利範圍中的術語具有下述含義。 DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

“C1-8烷基”指包括1至8個碳原子的直鏈烷基和含支鏈烷基，烷基指飽和的脂族烴基團。例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各種支鏈異構體等。 The "C 1-8 alkyl group" means a linear alkyl group having 1 to 8 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2 - dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-di Methyl butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methyl Hexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl , 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5 - dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof.

烷基可以是取代的或未取代的，當被取代時，取代基可以在任何可使用的連接點上被取代，較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyanide. Base, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 Substituted by a substituent of -NR 10 R 11 or -C(O)NR 11 .

“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基，“C3-8環烷基”指包括3至8個碳原子的環烷基，“5-10員環烷基”指包括5至10個碳原子的環烷基，例如：單環環烷基的非限制性實施例包含環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等。 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and " C3-8 cycloalkyl" refers to a cycloalkyl group containing from 3 to 8 carbon atoms, "5-10 membered ring.""Alkyl" means a cycloalkyl group comprising from 5 to 10 carbon atoms, for example, a non-limiting example of a monocyclic cycloalkyl group comprising a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclopentenyl group, a cyclohexyl group, Cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like.

多環環烷基包括螺環、稠環和橋環的環烷基。“螺環烷基”指單環之間共用一個碳原子(稱螺原子)的多環基團，這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基基或多螺環烷基，螺環烷基的非限制性實施例包含： Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

“稠環烷基”指系統中的每個環與體系中 的其他環共用毗鄰的一對碳原子的全碳多環基團，其中一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，稠環烷基的非限制性實施例包含： "Fused cycloalkyl" means an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:

“橋環烷基”指任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，橋環烷基的非限制性實施例包含： "Bridge cycloalkyl" refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上，其中與母體結構連接在一起的環為環烷基，非限制性實施例包括茚滿基、四氫萘基、苯並環庚烷基等。 The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.

環烷基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8. Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C (O) Substituted by NR 11 is substituted.

“雜環基”指飽和或部分不飽和單環或多 環環狀烴取代基，其中一個或多個環原子選自氮、氧或S(O)p(其中p是整數0、1、2)的雜原子，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。“5-10員雜環基”指包含5至10個環原子的環基，“3-8員雜環基”指包含3至8個環原子的環基。 "Heterocyclyl" means saturated or partially unsaturated monocyclic or poly a cyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer 0, 1, 2) heteroatom, but does not include -OO-, -OS- Or the ring portion of -SS-, the remaining ring atoms are carbon. The "5-10 membered heterocyclic group" means a ring group containing 5 to 10 ring atoms, and the "3-8 membered heterocyclic group" means a ring group containing 3 to 8 ring atoms.

單環環烷基的非限制性實施例包含吡咯烷基、哌啶基、哌嗪基、嗎啉基、硫基嗎啉基、高哌嗪基等。 Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.

多環環烷基包括螺環、稠環和橋環的雜環基。“螺雜環基”指單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子選自氮、氧或S(O)p(其中p是整數0、1、2)的雜原子，其餘環原子為碳。這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。根據環與環之間共用螺原子的數目將螺環烷基分為單螺雜環基、雙螺雜環基或多螺雜環基。螺環烷基的非限制性實施例包含： Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

“稠雜環基”指系統中的每個環與體系中的其他環共用毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子選自氮、氧或S(O)p(其中p是整數0至2)的雜原子，其餘環原子為碳。根據組成環的數目可以分為雙環、三環、四環或多環稠雜 環烷基，稠雜環基的非限制性實施例包含： "Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none The ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:

“橋雜環基”指任意兩個環共用兩個不直接連接的原子的多環雜環基團，這些可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統，其中一個或多個環原子選自氮、氧或S(O)p(其中p是整數0、1、2)的雜原子，其餘環原子為碳。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，橋環烷基的非限制性實施例包含： "Bridge heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O)p (where p is an integer 0, 1, 2) heteroatom, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

該雜環基環可以稠合於芳基、雜芳基或環烷基環上，其中與母體結構連接在一起的環為雜環基，非限制性實施例包含： The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:

雜環基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8 鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8. Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C (O) Substituted by NR 11 is substituted.

“芳基”指全碳單環或稠合多環(也就是共用毗鄰碳原子對的環)基團，具有共軛的π電子體系的多環(即其帶有相鄰對碳原子的環)基團，“C5-10芳基”指含有5-10個碳的全碳芳基，“5-10員芳基”指含有5-10個碳的全碳芳基，例如苯基和萘基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為芳基環，非限制性實施例包含： "Aryl" means an all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated π-electron system (ie, having a ring adjacent to a carbon atom) a group, "C 5-10 aryl" means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group" means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

芳基可以是取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1- 6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O) Substituted by a substituent of NR 11 .

“雜芳基”指包含1至4個雜原子的雜芳族體系，該雜原子包括氮、氧和S(O)p(其中p是整數0、1、 2)的雜原子，5-7員雜芳基指含有5-7個環原子的雜芳族體系，5-10員雜芳基指含有5-10個環原子的雜芳族體系，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。該雜芳基環可以稠合於芳基、雜環基或環烷基環上，其中與母體結構連接在一起的環為雜芳基環，非限制性實施例包含： "Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and S(O)p (where p is an integer 0, 1, 2) heteroatoms, 5-7 Heteroaryl refers to a heteroaromatic system containing 5-7 ring atoms, and a 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, such as furyl, thienyl, pyridyl, pyrrole A group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group or the like. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

雜芳基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8. Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C (O) Substituted by NR 11 is substituted.

“烯基”指由至少兩個碳原子和至少一個碳-碳雙鍵組成的如上述定義的烷基，C2-8鏈烯基指含有2-8個碳的直鏈或含支鏈烯基。例如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。 "Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C 2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

烯基可以是取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6 烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1- 6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O) Substituted by a substituent of NR 11 .

“炔基”指至少兩個碳原子和至少一個碳-碳三鍵組成的如上所定義的烷基，C2-8鏈炔基指含有2-8個碳的直鏈或含支鏈炔基。例如乙炔基、1-丙炔基、2-丙炔基、1-，2-或3-丁炔基等。 "Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons. . For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

炔基可以是取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1- 6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O) Substituted by a substituent of NR 11 .

“烷氧基”指-O-(烷基)，其中烷基的定義如上所述。C1-6烷氧基指含1-6個碳的烷基氧基，非限制性實施例包含甲氧基、乙氧基、丙氧基、丁氧基等。 "Alkoxy" means -O-(alkyl) wherein alkyl is as defined above. The C 1-6 alkoxy group means an alkyloxy group having 1 to 6 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.

烷氧基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代；“環烷基氧基”指和-O-(未取代的環烷基)，其中環烷基的定義如上所述。C3-8環烷基氧基指含3-8個碳的環烷基-氧基，非限制性實施例包含環丙基氧基、環 丁基氧基、環戊基氧基、環己基氧基等。 The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8. Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C (O) Substituent of NR 11 is substituted; "cycloalkyloxy" means -O-(unsubstituted cycloalkyl), wherein cycloalkyl is as defined above. C 3-8 cycloalkyloxy refers to a cycloalkyl-oxy group having 3-8 carbons, and non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyl Oxyl and the like.

烷氧基可以是視需要取代的或未取代的，當被取代時，取代基較佳為一個或多個以下基團，獨立地選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代。 The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8. Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclic, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C (O) Substituted by NR 11 is substituted.

“鹵素取代的C1-6烷基”指烷基上的氫視需要的被氟、氯、溴、碘原子取代的1-6個碳烷基基團，例如二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。 "Halogen-substituted C 1-6 alkyl" means a 1-6 alkylalkyl group, such as difluoromethyl or dichloromethyl, substituted by a fluorine, chlorine, bromine or iodine atom as required for the hydrogen on the alkyl group. Base, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

“鹵素取代的C1-6烷氧基”烷基上的氫視需要的被氟、氯、溴、碘原子取代的1-6個碳烷氧基基團。例如二氟甲氧基、二氯甲氧基、二溴甲氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基等。 The hydrogen on the "halogen-substituted C 1-6 alkoxy"alkyl group is optionally a 1-6 carboalkoxy group substituted with a fluorine, chlorine, bromine or iodine atom. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

“鹵素”指氟、氯、溴或碘。 "Halogen" means fluoro, chloro, bromo or iodo.

“羥基”指-OH基團。 "Hydroxy" refers to an -OH group.

“硝基”指-NO2基團。 "Nitro" refers to a -NO 2 group.

“-S(O)pR9”指R9取代的硫、亞硫醯基、硫醯基。 "-S(O)pR 9 " refers to an R 9 -substituted sulfur, sulfinyl group, thiol group.

“-C(O)R9”指R9取代的羰基。 "-C(O)R 9 " refers to a carbonyl group substituted with R 9 .

“-C(O)OR9”指R9取代的氧基羰基。 "-C(O)OR 9 " refers to an R 9 -substituted oxycarbonyl group.

“-NR10R11”指R10、R11取代的胺基。 "-NR 10 R 11 " refers to an amine group substituted with R 10 and R 11 .

“-C(O)NR11”指R11取代的醯胺基。 "-C(O)NR 11 " refers to an arylamine group substituted with R 11 .

“視需要”或“視需要地”意味著隨後所描述地事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生的場合。例如，“視需要被烷基取代的雜環基團”意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group. .

“取代的”指基團中的一個或多個氫原子，較佳為最多5個，更較佳為1至3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻，取代基僅處在它們的可能的化學位置，本領域技術人員能夠在不付出過多努力的情況下確定(通過實驗或理論)可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

“藥物組成物”表示含有一種或多種本文所述化合物或其生理學上/可藥用鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。藥物組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.

下面結合實施例對本發明做進一步詳細、完整地說明，但決非限制本發明，本發明也並非僅局限於實施例的內容。 The present invention is further described in detail with reference to the accompanying drawings, but by no way of limitation,

實施例1：5-氯-(2-異丙氧基-5-甲基-4-(哌啶-4-基)苯基)-(2-(異丙基磺醯基)吡啶-3-基)嘧啶-2,4-二胺 Example 1: 5-Chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-(2-(isopropylsulfonyl)pyridine-3- Pyrimidine-2,4-diamine

第一步：4-(5-異丙氧基-2-甲基-4-硝基苯基)-3,6-二氫 吡啶-1(2H)-羧酸第三丁酯的製備 First step: 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydro Preparation of pyridine-1(2H)-carboxylic acid tert-butyl ester

將化合物1-氯-5-異丙氧基-2-甲基-4-硝基苯(2.5g,10.89mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯(3.7g,11.97mmol)，碳酸鉀(4.5g,26.78mmol)和Pd(dppf)Cl2(398mg,0.55mmol)溶於1,4-二噁烷中。氮氣置換保護，加熱至150℃反應。5小時後，旋去反應溶劑，加水與二氯甲烷，分離水層與有機層，水相用二氯甲烷萃取三次。合併有機相，無水硫酸鈉乾燥。蒸除溶劑，管柱層析分離純化得到產品。 1-Chloro-5-isopropoxy-2-methyl-4-nitrobenzene (2.5 g, 10.89 mmol), 4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.7 g, 11.97 mmol), potassium carbonate (4.5 g, 26.78 mmol) And Pd(dppf)Cl 2 (398 mg, 0.55 mmol) was dissolved in 1,4-dioxane. Nitrogen replacement protection, heating to 150 ° C reaction. After 5 hours, the reaction solvent was stirred, water and dichloromethane were added, and the aqueous layer and organic layer were separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off, and the product was separated and purified by column chromatography.

LCMS：t=4.85min,347.1(M+H+). LCMS: t = 4.85 min, 347.1 (M+H + ).

第二步：4-(4-胺基-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯的製備 Second step: Preparation of tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate

將化合物4-(5-異丙氧基-2-甲基-4-硝基苯基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯(3.4g,0.26mmol)溶於甲醇中，加入鈀/碳(400mg)。氫氣置換，氫氣氛圍下室溫攪拌過夜。過濾，蒸除甲醇，得化合物4-(4-胺基-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯(3.3g)。 The compound 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.4 g, 0.26 mmol ) Dissolved in methanol and added palladium on carbon (400 mg). The hydrogen was replaced and stirred at room temperature overnight under a hydrogen atmosphere. Filtration and evaporation of methanol gave the title compound (3-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (3.3 g).

LCMS：t=4.16min,349.0(M+H+). LCMS: t = 4.16 min, 349.0 (M+H + ).

第三步：2-異丙基巰基-3-硝基吡啶的製備 The third step: preparation of 2-isopropyl decyl-3-nitropyridine

將2-氟-3-硝基吡啶(500mg,3.52mmol)，碳酸鉀(973mg,7.04mmol)置於100mL圓底瓶中，加入15毫升DMF。在攪拌下，加入異丙硫醇(0.36mL,3.87mmol)，將混合物在室溫下反應1小時，反應完畢後旋去反應溶劑，所得粗品經水洗，乙酸乙酯萃取，乾燥後濃縮，再經管柱層析得產物2-異丙基巰基-3-硝基吡啶(660mg，產率95%)。 2-Fluoro-3-nitropyridine (500 mg, 3.52 mmol), potassium carbonate (973 mg, 7.04 mmol) was placed in a 100 mL round bottom flask, and 15 ml of DMF was added. Under stirring, isopropyl mercaptan (0.36 mL, 3.87 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solvent was spun off, and the obtained crude product was washed with water, ethyl acetate, dried and concentrated. The product was chromatographed to give 2-isopropyl-mercapto-3-nitropyridine (660 mg, yield 95%).

1H NMR(400MHz,CDCl3)δ 8.61(dd,J=4.8，1.6Hz,1H),8.40(dd,J=8.4,1.6Hz,1H),7.10(dd,J=8.4,4.8Hz,1H),4.13-4.06(m,1H),1.35(d,J=6.8Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (dd, J = 8.4, 1.6 Hz, 1H), 7.10 (dd, J = 8.4, 4.8 Hz, 1H) ), 4.3-4.6.0 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H).

LCMS：t=4.31min,198.9(M+H+). LCMS: t = 4.31 min, 198.9 (M+H + ).

第四步：2-異丙基碸基-3-硝基吡啶的製備 The fourth step: preparation of 2-isopropyl decyl-3-nitropyridine

將2-異丙基巰基-3-硝基吡啶(660mg,3.33mmol)和mCPBA(85%,2.2g,9.99mmol)置於100mL圓底瓶中，加入15毫升DCM。將混合物在室溫下攪拌過夜，反應完畢後旋去反應溶劑，所得粗品依次用飽和亞硫酸鈉溶液，飽和碳酸鉀溶液，飽和食鹽水洗，二氯甲烷萃取，乾燥，旋乾，再經管柱層析得產物2-異丙基碸基-3-硝基吡啶(700mg，產率91%)。 2-Isopropylguanidino-3-nitropyridine (660 mg, 3.33 mmol) and mCPBA (85%, 2.2 g, 9.99 mmol) were placed in a 100 mL round bottom flask and 15 mL DCM was added. The mixture is stirred at room temperature overnight. After the reaction is completed, the reaction solvent is evaporated. The obtained crude product is washed with saturated sodium sulfite solution, saturated potassium carbonate solution, saturated brine, extracted with dichloromethane, dried, The product 2-isopropylmercapto-3-nitropyridine (700 mg, yield 91%).

1H NMR(400MHz,CDCl3)δ 8.84(dd,J=4.4,1.6Hz,1H), 8.06(dd,J=8.4,1.6Hz,1H),7.68(dd,J=8.0,4.4Hz,1H),4.03-3.96(m,1H),1.36(d,J=6.8Hz,6H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.84 (dd, J = 4.4, 1.6 Hz, 1H), 8.06 (dd, J = 8.4, 1.6 Hz, 1H), 7.68 (dd, J = 8.0, 4.4 Hz, 1H) ), 4.03-3.96 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

LCMS：t=3.39min,201.0(M+H+). LCMS: t = 3.39 min, 201.0 (M+H + ).

第五步：2-異丙基碸基-3-胺基吡啶的製備 Step 5: Preparation of 2-isopropylmercapto-3-aminopyridine

將2-異丙基碸基-3-硝基吡啶(700mg,2.18mmol)置於100mL氫化瓶中，加入15毫升甲醇，氮氣置換後將100mg鈀/碳加入到瓶中，用氫氣球置換後攪拌過夜，反應完畢後將溶液過濾，濾液減壓旋乾即得產品(600mg，產率90%)。 2-Isopropylguanidino-3-nitropyridine (700 mg, 2.18 mmol) was placed in a 100 mL hydrogenation flask, and 15 ml of methanol was added. After replacing with nitrogen, 100 mg of palladium/carbon was added to the bottle and replaced with a hydrogen balloon. After stirring overnight, the solution was filtered, and the filtrate was dried under reduced pressure to give a product (600 mg, yield 90%).

LCMS：t=2.85min,201.0(M+H+). LCMS: t = 2.85 min, 201.0 (M+H + ).

第六步：2,5-二氯-N-(2-(異丙基磺醯基)吡啶-3-基)嘧啶-4-胺的製備 Step 6: Preparation of 2,5-dichloro-N-(2-(isopropylsulfonyl)pyridin-3-yl)pyrimidine-4-amine

將2-異丙基碸基-3-胺基吡啶(200mg,1.0mmol)溶於DMF(6mL)中，在0℃下慢慢加入NaH(44mg,1.1mmol)。加完後，反應液繼續在0℃下攪拌半小時，再將2,5,6-三氯嘧啶(201mg,1.1mmol)在0℃下滴入反應液。滴畢，混合物自然升至室溫攪拌過夜。完畢後，加入200mL水，並用EA萃取(30mL*3)，合併有機相後乾燥，旋去反應溶劑，所得粗品經管柱層析得產物(90mg，產率26%)。 2-Isopropyl-mercapto-3-aminopyridine (200 mg, 1.0 mmol) was dissolved in DMF (6 mL)EtOAc. After the addition, the reaction mixture was further stirred at 0 ° C for half an hour, and 2,5,6-trichloropyrimidine (201 mg, 1.1 mmol) was added dropwise to the reaction mixture at 0 °C. After the dropwise addition, the mixture was naturally stirred to room temperature and stirred overnight. After completion, 200 mL of water was added, and extracted with EA (30 mL*3). The organic phase was combined, dried, and the solvent was evaporated. The obtained crude product was obtained by column chromatography (90 mg, yield 26%).

1H NMR(400MHz,CDCl3)δ 10.48(s,1H),9.17(dd,J= 8.4,1.6Hz,1H),8.38(dd,J=4.4,2.8Hz,1H),8.26(s,1H),7.55(dd,J=8.8,3.2Hz,1H),3.90-3.87(m,1H),1.31(d,J=6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ 10.48 (s, 1H), 9.17 (dd, J = 8.4,1.6Hz, 1H), 8.38 (dd, J = 4.4,2.8Hz, 1H), 8.26 (s, 1H ), 7.55 (dd, J = 8.8, 3.2 Hz, 1H), 3.90-3.87 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H).

LCMS：t=3.95min,346.9(M+H+). LCMS: t = 3.95 min, 346.9 (M+H + ).

第七步：4-(4-((5-氯-4-((2-(異丙基磺醯基)吡啶-3-基)胺基)嘧啶-2-基)胺基)-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯的製備 Step 7: 4-(4-((5-Chlorosulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-5- Preparation of tert-butyl isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid

將2,5-二氯-N-(2-(異丙基磺醯基)吡啶-3-基)嘧啶-4-胺(90mg,0.26mmol)，4-(4-胺基-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯(100mg,0.28mmol)，醋酸鈀(6mg,20μmol)，Xantphos(17mg,22μmol)，醋酸銫(253mg,0.78mmol)置於10mL微波管中，加入5毫升二噁烷，氮氣置換後將混合物微波加熱至130度反應半小時，反應完畢後旋去反應溶劑，所得粗品經管柱層析得產物(60mg，產率35%)。 2,5-Dichloro-N-(2-(isopropylsulfonyl)pyridin-3-yl)pyrimidin-4-amine (90 mg, 0.26 mmol), 4-(4-amino-5-iso) propan-2-methylphenyl) piperidine-1-carboxylic acid tert-butyl ester (100mg, 0.28mmol), palladium acetate (6mg, 20 μ mol), Xantphos (17mg, 22 μ mol), cesium acetate (253 mg, 0.78 mmol) was placed in a 10 mL microwave tube, 5 ml of dioxane was added, and after nitrogen substitution, the mixture was microwave-heated to 130 °C for half an hour. After the reaction was completed, the reaction solvent was spun off, and the obtained crude product was subjected to column chromatography to obtain a product. (60 mg, yield 35%).

LCMS：t=5.47min,658.9(M+H+). LCMS: t = 5.47 min, 658.9 (M+H + ).

第八步：5-氯-(2-異丙氧基-5-甲基-4-(哌啶-4-基)苯基)-(2-(異丙基磺醯基)吡啶-3-基)嘧啶-2,4-二胺的製備 Step 8: 5-Chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-(2-(isopropylsulfonyl)pyridine-3- Of pyrimidine-2,4-diamine

將4-(4-((5-氯-4-((2-(異丙基磺醯基)吡啶-3-基)胺基)嘧啶-2-基)胺基)-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯(60mg,91μmol)溶於4毫升DCM中，在室溫下滴入TFA(1mL)並攪拌半小時，反應完畢後旋去反應溶劑，所得粗品經管柱層析和製備TLC純化得產物(30mg，產率59%). 4-(4-((5-chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-5-isopropyloxy -2-methylphenyl) piperidine-1-carboxylic acid tert-butyl ester (60mg, 91 μ mol) dissolved in 4 ml DCM, was added dropwise TFA (1mL) and stirred at room temperature for half an hour, the reaction After completion, the reaction solvent was spun off, and the obtained crude product was purified by column chromatography and preparative TLC (30 mg, yield 59%).

1H NMR(400MHz,CDCl3)：δ 10.01(s,1H),9.14(dd,J=8.8,1.2Hz,1H),8.31(dd,J=4.0,2.8Hz,1H),7.90(s,1H),7.43(s,1H),7.40-7.37(m,1H),6.76(s,1H),4.55-4.52(m,1H),3.89-3.85(m,1H),3.53-3.50(m,2H),2.96-2.85(m,3H),2.15(s,3H),2.05-2.02(m,2H),1.89-1.86(m,2H),1.33(d,J=7.2Hz,6H),1.30(d,J=6.4Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ 10.01 (s, 1H), 9.14 (dd, J = 8.8,1.2Hz, 1H), 8.31 (dd, J = 4.0,2.8Hz, 1H), 7.90 (s, 1H), 7.43 (s, 1H), 7.40-7.37 (m, 1H), 6.76 (s, 1H), 4.55-4.52 (m, 1H), 3.89-3.85 (m, 1H), 3.53-3.50 (m, 2H), 2.96-2.85 (m, 3H), 2.15 (s, 3H), 2.05-2.02 (m, 2H), 1.89-1.86 (m, 2H), 1.33 (d, J = 7.2 Hz, 6H), 1.30 (d, J = 6.4 Hz, 6H).

LCMS：t=3.69min,558.9(M+H+). LCMS: t = 3.69 min, 558.9 (M+H + ).

實施例2：5-二氟甲氧基-(2-異丙氧基-5-甲基-4-哌啶-4-基-苯基)-[2-(丙烷-2-磺醯基)-苯基]-嘧啶-2,4-二胺的製備 Example 2: 5-Difluoromethoxy-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-[2-(propane-2-sulfonyl) -Phenyl]-pyrimidine-2,4-diamine preparation

第一步：2-氯-N-(2-(異丙基磺醯基)苯基)-5-甲氧基嘧啶-4-胺的製備 First step: Preparation of 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-methoxypyrimidine-4-amine

將2-異丙基碸基苯胺(200mg,0.99mmol)溶 於DMF(8mL)中，在0℃下慢慢加入NaH(29mg,1.2mmol)，加完後反應液繼續在0℃下攪拌半小時，再將2,6-二氯-5-甲氧基嘧啶(197mg,1.1mmol)在0℃下滴入反應液，滴畢，混合物自然升至室溫攪拌4小時。完畢後加入200mL水並用DCM萃取(30mL*3)，合併有機相後乾燥，旋去反應溶劑，所得粗品經管柱層析得產物(90mg，產率26%)。 Dissolve 2-isopropyl decyl aniline (200 mg, 0.99 mmol) NaH (29 mg, 1.2 mmol) was slowly added at 0 ° C in DMF (8 mL). After the addition, the reaction mixture was stirred at 0 ° C for half an hour, then 2,6-dichloro-5-methoxy The pyrimidine (197 mg, 1.1 mmol) was added dropwise to the reaction mixture at 0 ° C, and the mixture was stirred and the mixture was allowed to warm to room temperature for 4 hours. After completion, 200 mL of water was added and extracted with DCM (30 mL*3). The organic phase was combined, dried, and the solvent was evaporated. The obtained crude product was obtained by column chromatography (90 mg, yield 26%).

1H NMR(400MHz,CDCl3)：δ 9.50(s,1H),9.87(s,1H),8.68(d,J=8.4,1.2Hz,1H),7.81(dd,J=8.0,1.6Hz,1H),7.76(s,1H),7.64-7.60(m,1H),7.17-7.15(m,1H),3.94(s,3H),3.17-3.10(m,1H),1.22(d,J=6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ 9.50 (s, 1H), 9.87 (s, 1H), 8.68 (d, J = 8.4,1.2Hz, 1H), 7.81 (dd, J = 8.0,1.6Hz, 1H), 7.76 (s, 1H), 7.64-7.60 (m, 1H), 7.17-7.15 (m, 1H), 3.94 (s, 3H), 3.17-3.10 (m, 1H), 1.22 (d, J = 6.8Hz, 6H).

LCMS：t=4.10min,341.8(M+H+). LCMS: t = 4.10 min, 341.8 (M+H + ).

第二步：2-氯-4-((2-(異丙基磺醯基)苯基)胺基)嘧啶-5-酚的製備 Step 2: Preparation of 2-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-5-phenol

將化合物2-氯-N-(2-(異丙基磺醯基)苯基)-5-甲氧基嘧啶-4-胺(50mg,0.15mmol)溶于無水DCM(10mL)中，在0℃下慢慢加入BBr3(0.2mL,4N in DCM,0.75mmol)，加完後反應液自然升至室溫攪拌過夜。反應完畢後在0℃下慢慢加入甲醇(3mL)淬滅反應，再加入500mL水洗並用DCM萃取(40mL*3)，合併有機相後乾燥，旋去反應溶劑，所得粗品經管柱層析得產物淡黃色固體(30mg，產率52%)。 The compound 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-methoxypyrimidin-4-amine (50 mg, 0.15 mmol) was dissolved in anhydrous DCM (10 mL) BBr 3 (0.2 mL, 4 N in DCM, 0.75 mmol) was slowly added at ° C. After the addition, the reaction mixture was allowed to warm to room temperature overnight. After completion of the reaction, the reaction was quenched by slowly adding methanol (3 mL) at 0 ° C, and then washed with 500 mL of water and extracted with DCM (40 mL*3). The organic phase was combined, dried, and the solvent was evaporated to give a crude product obtained by column chromatography. Light yellow solid (30 mg, yield 52%).

LCMS：t=3.68min,327.9(M+H+). LCMS: t = 3.68 min, 327.9 (M+H + ).

第三步：2-氯-5-(二氟甲氧基)-N-(2-(異丙基磺醯基)苯基)嘧啶-4-胺的製備 The third step: preparation of 2-chloro-5-(difluoromethoxy)-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine

將2-氯-4-((2-(異丙基磺醯基)苯基)胺基)嘧啶-5-酚(20mg,61μmol)，二氟一氯醋酸鈉(28mg,0.18mmol)，碳酸鉀(25mg,0.18mmol)置於10mL微波管中，加入3毫升DMF和3毫升水，氮氣置換後將混合物微波加熱至120度反應1小時，反應完畢後旋去反應溶劑，所得粗品經管柱層析得產物(10mg，產率43%)。 2-Chloro-4 - ((2- (isopropylamino sulfo acyl) phenyl) amino) pyrimidin-5-ol (20mg, 61 μ mol), chlorodifluoromethane sodium acetate (28mg, 0.18mmol) Potassium carbonate (25 mg, 0.18 mmol) was placed in a 10 mL microwave tube, and 3 ml of DMF and 3 ml of water were added. After replacing with nitrogen, the mixture was microwave-heated to 120 degrees for 1 hour. After the reaction was completed, the reaction solvent was rotated to obtain a crude product. Column chromatography gave the product (10 mg, yield 43%).

LCMS：t=4.29min,377.8(M+H+). LCMS: t = 4.29 min, 377.8 (M+H + ).

第四步：4-(4-((5-(二氟甲氧基)-4-((2-(異丙基磺醯基)苯基)胺基)嘧啶-2-基)胺基)-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯的製備 Fourth step: 4-(4-((5-(difluoromethoxy)-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino) Preparation of -5-isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester

將化合物2-氯-5-(二氟甲氧基)-N-(2-(異丙基磺醯基)苯基)嘧啶-4-胺(10mg,26μmol)，4-(4-胺基-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯(14mg,39μmol)，醋酸鈀 (1mg,2.08μmol)，Xantphos(2mg,2.6μmol)，醋酸銫(25mg,79μmol)置於10mL微波管中，加入2毫升二噁烷，氮氣置換後將混合物微波加熱至130度反應半小時，反應完畢後旋去反應溶劑，所得粗品經管柱層析得產物(5mg，產率27%)。 The compound 2-chloro-5- (difluoromethoxy) -N- (2- (isopropyl-sulfo acyl) phenyl) pyrimidin-4-amine (10mg, 26 μ mol), 4- (4- amino-5- isopropoxy-2-methylphenyl) piperidine-1-carboxylic acid tert-butyl ester (14mg, 39 μ mol), palladium acetate (1mg, 2.08 μ mol), Xantphos (2mg, 2.6 μ mol), cesium acetate (25mg, 79 μ mol) was placed in a 10mL microwave tube was added 2 ml of dioxane, the mixture was purged with nitrogen a microwave reactor was heated to 130 degrees for half an hour, the reaction solvent was removed by rotary evaporation after completion of the reaction, The obtained crude product was obtained by column chromatography to afford product (5mg, yield 27%).

LCMS：t=5.36min,89.9(M+H+). LCMS: t = 5.36 min, 89.9 (M+H + ).

第五步：5-二氟甲氧基-(2-異丙氧基-5-甲基-4-哌啶-4-基-苯基)-[2-(丙烷-2-磺醯基)-苯基]-嘧啶-2,4-二胺的製備 Step 5: 5-Difluoromethoxy-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-[2-(propane-2-sulfonyl) -Phenyl]-pyrimidine-2,4-diamine preparation

將4-(4-((5-(二氟甲氧基)-4-((2-(異丙基磺醯基)苯基)胺基)嘧啶-2-基)胺基)-5-異丙氧基-2-甲基苯基)哌啶-1-羧酸第三丁酯(5mg,7.2μmol)溶於4毫升DCM中，在室溫下滴入TFA(1mL)並攪拌半小時，反應完畢後旋去反應溶劑，所得粗品經管柱層析和製備TLC純化得產物(2.8mg，產率65%)。 4-(4-((5-(Difluoromethoxy)-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5- isopropoxy-2-methylphenyl) piperidine-1-carboxylic acid tert-butyl ester (5mg, 7.2 μ mol) dissolved in 4 ml DCM, was added dropwise TFA (1mL) at room temperature and stirred for half After the completion of the reaction, the reaction solvent was evaporated, and the obtained crude product was purified by column chromatography and preparative TLC (2.8 mg, yield: 65%).

1H NMR(400MHz,CDCl3)：δ 9.50(s,1H),8.63(d,J=8.4Hz,1H),8.03(d,J=4.8Hz,2H),7.83(dd,J=8.0,2.8Hz,1H),7.55-7.45(m,2H),7.16-7.15(m,1H),6.92(s,0.2 H),6.74(s,1 H),6.71(s,0.2 H),6.53(s,0.4 H),6.35(s,0.2 H),4.53-4.50(m,1H),3.48-3.42(m,2H),3.27-3.21(m,1H), 2.92-2.78(m,3H),2.13(s,3H),1.99-1.77(m,4H),1.27(d,J=6Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ 9.50 (s, 1H), 8.63 (d, J = 8.4Hz, 1H), 8.03 (d, J = 4.8Hz, 2H), 7.83 (dd, J = 8.0, 2.8 Hz, 1H), 7.55-7.45 (m, 2H), 7.16-7.15 (m, 1H), 6.92 (s, 0.2 H), 6.74 (s, 1 H), 6.71 (s, 0.2 H), 6.53 ( s, 0.4 H), 6.35 (s, 0.2 H), 4.53-4.50 (m, 1H), 3.48-3.42 (m, 2H), 3.27-3.21 (m, 1H), 2.92-2.78 (m, 3H), 2.13 (s, 3H), 1.99-1.77 (m, 4H), 1.27 (d, J = 6 Hz, 6H).

LCMS：t=3.64min，590.0(M+H+). LCMS: t = 3.64 min, 590.0 (M+H + ).

實施例3：5-氯-2-[2-異丙氧基-5-甲基-4-(1-甲基-哌啶-4-基)-苯基]-4-[2-(丙烷-2-磺醯基)-吡啶-3-基]-嘧啶-2,4-二胺的製備 Example 3: 5-Chloro-2-[2-isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenyl]-4-[2-(propane Preparation of -2-sulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamine

將化合物5-氯-(2-異丙氧基-5-甲基-4-(哌啶-4-基)苯基)-(2-(異丙基磺醯基)吡啶-3-基)嘧啶-2,4-二胺(15mg,26.8μmol)溶解在乾燥的無水甲醇中，在室溫下加入多聚甲醛(4mg,134μmol)，氰基硼氫化鈉(3.37mg,53.6μmol)和催化量的醋酸。混合物在室溫下攪拌過夜，用TLC和LCMS檢測反應。向反應液中滴加1N NaOH水溶液淬滅反應。減壓蒸去有機溶劑，並將殘留物分散在二氯甲烷中，並用水和食鹽水洗淨，有機相用無水硫酸鎂乾燥，過濾旋乾得粗產品，經製備TLC板分離得目標化合物5-氯-2-[2-異丙氧基-5-甲基-4-(1-甲基-哌啶-4-基)-苯基]-4-[2-(丙烷-2-磺醯基)-吡啶-3-基]-嘧啶-2,4-二胺(5mg，30%)。 The compound 5-chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-(2-(isopropylsulfonyl)pyridin-3-yl) pyrimidine-2,4-diamine (15mg, 26.8 μ mol) was dissolved in dry anhydrous methanol, was added paraformaldehyde (4mg, 134 μ mol) at room temperature, sodium cyanoborohydride (3.37mg, 53.6 μ Mol) and a catalytic amount of acetic acid. The mixture was stirred at room temperature overnight and the reaction was checked by TLC and LCMS. The reaction was quenched by dropwise addition of a 1N aqueous NaOH solution. The organic solvent was evaporated under reduced pressure, and the residue was evaporated, evaporated, mjjjjjjjjjjjjjjj Chloro-2-[2-isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenyl]-4-[2-(propane-2-sulfonyl) )-pyridin-3-yl]-pyrimidine-2,4-diamine (5 mg, 30%).

1H NMR(400MHz,CDCl3)：δ 10.60(s,1H),10.06(s,1H),9.20(dd,J=8.7,1.3Hz,1H),8.93(dd,J=8.6,1.3Hz,1H),8.50(t,J=4.3,1.4Hz,2H),8.38(d,J=4.3,1.4Hz,1H),8.21(s,1H),8.19(s,1H),7.96(s,1H),7.58(s,1H),7.53(s,1H), 7.48(dd,J=8.7,4.4Hz,1H),7.42(dd,J=8.6,4.4Hz,1H),6.95(s,1H),6.84(s,1H),4.76-4.55(m,2H),4.36(s,1H),4.10-3.87(m,2H),3.68(s,4H),3.12-2.79(m,11H),2.45-2.31(m,5H),2.22(s,3H),2.17(s,3H),2.07-1.99(m,6H),1.46-1.31(m,22H). 1 H NMR (400MHz, CDCl 3 ): δ 10.60 (s, 1H), 10.06 (s, 1H), 9.20 (dd, J = 8.7,1.3Hz, 1H), 8.93 (dd, J = 8.6,1.3Hz, 1H), 8.50 (t, J = 4.3, 1.4 Hz, 2H), 8.38 (d, J = 4.3, 1.4 Hz, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H) ), 7.58 (s, 1H), 7.53 (s, 1H), 7.48 (dd, J = 8.7, 4.4 Hz, 1H), 7.42 (dd, J = 8.6, 4.4 Hz, 1H), 6.95 (s, 1H) , 6.84 (s, 1H), 4.76-4.55 (m, 2H), 4.36 (s, 1H), 4.10-3.87 (m, 2H), 3.68 (s, 4H), 3.12-2.79 (m, 11H), 2.45 -2.31 (m, 5H), 2.22 (s, 3H), 2.17 (s, 3H), 2.07-1.99 (m, 6H), 1.46-1.31 (m, 22H).

LCMS：t=3.60min,612.3(M+K+). LCMS: t = 3.60 min, 612.3 (M+K + ).

實施例4：1-[4-(4-{5-氯-4-[2-(丙烷-2-磺醯基)-吡啶-3-基胺基]-嘧啶-2-基胺基}-5-異丙氧基-2-甲基-苯基)-哌啶-1-基]-乙酮的製備 Example 4: 1-[4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}- Preparation of 5-isopropoxy-2-methyl-phenyl)-piperidin-1-yl]-ethanone

第一步：1-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮的製備 First step: 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 Preparation of (2H)-yl]ethanone

4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,6-二氫吡啶-1(2H)-羧酸第三丁酯(1.0g,3.2mmol)溶於二氯甲烷中，三氟乙酸(4mL)加入後室溫攪拌2小時，直接蒸出溶劑得無色油狀物，冰水浴下溶於二氯甲烷中，加入三乙胺(2mL,14.3mmol)，緩慢滴加乙醯氯(1.0mL,8mmol)，自由升到室溫並繼續攪拌2小時。往體系加入30mL的水和30mL的二氯甲烷，分去水相，蒸出溶劑得橙黃色固體(700mg，86%)。 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid Tributyl ester (1.0 g, 3.2 mmol) was dissolved in dichloromethane, and then added with trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 2 hr. Triethylamine (2 mL, 14.3 mmol) was added, and ethyl acetate (1.0 mL, 8 mmol) was slowly added dropwise, and the mixture was allowed to warm to room temperature and stirring was continued for 2 hours. 30 mL of water and 30 mL of dichloromethane were added to the system, the aqueous phase was separated, and the solvent was evaporated to give an orange solid (700 mg, 86%).

第二步：1-{4-[2-甲基-4-硝基-5-(丙烷-2-氧基)苯基]哌啶-1-基}-乙酮的製備 Second step: Preparation of 1-{4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone

在氮氣保護下，1-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,6-二氫吡啶-1(2H)-基]乙酮(601.4mg,2.3mmol)溶於10mL的二噁烷/水(3：1)中，依次加入1-氯-5-異丙氧基-2-甲基-4-硝基苯(500.0mg,2.3mmol)、Pd(dppf)Cl2(80mg,0.11mmol)和碳酸鉀(902mg,6.5mmol)，反應體系在150度下微波攪拌1小時，蒸出溶劑，直接經管柱層析得1-{4-[2-甲基-4-硝基-5-(丙烷-2-氧基)苯基]哌啶-1-基}-乙酮(600mg,77%)。 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-protected under nitrogen 1(2H)-yl]ethanone (601.4 mg, 2.3 mmol) was dissolved in 10 mL of dioxane / water (3:1), then 1-chloro-5-isopropoxy-2-methyl- 4-nitrobenzene (500.0 mg, 2.3 mmol), Pd(dppf)Cl 2 (80 mg, 0.11 mmol), and potassium carbonate (902 mg, 6.5 mmol). The reaction was stirred at 150 °C for 1 hour, and the solvent was evaporated. Direct column chromatography gave 1-{4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone (600 mg, 77%) ).

第三步：1-{4-[4-胺基-2-甲基-5-(丙烷-2-氧基)苯基]哌啶-1-基}-乙酮的製備 Third step: Preparation of 1-{4-[4-amino-2-methyl-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone

將1-{4-[2-甲基-4-硝基-5-(丙烷-2-氧基)苯基]哌啶-1-基}-乙酮(600mg)溶於10mL的甲醇中，氮氣保護下加入鈀/碳催化劑，室溫攪拌過夜，過濾除去固體，濾液直接蒸乾得無色液體(530mg，95%)。 1-{4-[2-Methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone (600 mg) was dissolved in 10 mL of methanol. The palladium on carbon catalyst was added under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight, and the solid was filtered, and the filtrate was evaporated to dryness (yield: 530 mg, 95%).

第四步：1-[4-(4-{5-氯-4-[2-(丙烷-2-磺醯基)-吡啶-3-基胺基]-嘧啶-2-基胺基}-5-異丙氧基-2-甲基-苯基)-哌啶-1-基]-乙酮的製備 Fourth step: 1-[4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}- Preparation of 5-isopropoxy-2-methyl-phenyl)-piperidin-1-yl]-ethanone

將化合物2-氯-5-(二氟甲氧基)-N-(2-(異丙基磺醯基)苯基)嘧啶-4-胺(60mg,0.173mmol)溶解在乾燥的DMF(2mL)中，室溫下加入N,N-二甲基異丙胺(89.59mg,693μmol)，TBTU(58mg,181.9μmol)，並室溫下攪拌過夜，加水稀釋反應液，用乙酸乙酯萃取，合併有機相並用食鹽水洗3~4次，用無水硫酸鈉乾燥有機相，過濾，旋乾，將得到的殘留物溶解於乾燥的二噁烷(5mL)，並向其中加入1-{4-[4-胺基-2-甲基-5-(丙烷-2-氧基)苯基]哌啶-1-基}-乙酮(62.5mg,215μmol)，對甲苯磺酸(46.3mg,269μmol)，加熱到150℃反應過夜，用LCMS檢測反應。將反應液用乙酸乙酯稀釋，用飽和碳酸氫鈉水溶液洗，並用食鹽水洗，將有機相用無水硫酸鈉乾燥，過濾，蒸出溶劑得到粗產品，經管柱層析分離得到1-[4-(4-{5-氯-4-[2-(丙烷-2-磺醯基)-吡啶-3-基胺基]-嘧啶-2-基胺基}-5-異丙氧基-2-甲基-苯基)-哌啶-1-基]-乙酮(23mg,21.3%)。 The compound 2-chloro-5-(difluoromethoxy)-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine (60 mg, 0.173 mmol) was dissolved in dry DMF (2 mL) ) was added at room temperature N, N- dimethyl-diisopropylamine (89.59mg, 693 μ mol), TBTU (58mg, 181.9 μ mol), and stirred at room temperature overnight, the reaction was diluted with water, extracted with ethyl acetate The organic phase was extracted and washed with brine for 3 to 4 times. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness, and the residue was dissolved in dry dioxane (5 mL) - [4-amino-2-methyl-5- (propane-2-yloxy) phenyl] piperidin-1-yl} - ethanone (62.5mg, 215 μ mol), p-toluenesulfonic acid (46.3 mg, 269 μ mol), the reaction was heated to 150 deg.] C overnight, the reaction was detected by LCMS. The reaction mixture was diluted with EtOAc. EtOAc (EtOAc m. (4-{5-Chloro-4-[2-(propan-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2- Methyl-phenyl)-piperidin-1-yl]-ethanone (23 mg, 21.3%).

1H NMR(400MHz,CDCl3)：δ 10.11(s,1H),9.22(dd,J=8.7,1.2Hz,1H),8.39(dd,J=4.3,1.3Hz,1H),8.18(s,1H),7.92(s,1H),7.57(s,1H),7.45(dd,J=8.7,4.4Hz,1H),6.71(s,1H),4.83(d,J=13.3Hz,1H),4.58-4.53(m,1H),3.98-3.93(m 2H),3.23-3.20(m,1H),2.93-2.92(m 1H),2.68-2.62(m,1H),2.24(s,3H),2.16(s,3H),1.87-1.80(m,2H),1.63-1.56 (m,2H),1.41-1.36(m,12H). 1 H NMR (400MHz, CDCl 3 ): δ 10.11 (s, 1H), 9.22 (dd, J = 8.7,1.2Hz, 1H), 8.39 (dd, J = 4.3,1.3Hz, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.57 (s, 1H), 7.45 (dd, J = 8.7, 4.4 Hz, 1H), 6.71 (s, 1H), 4.83 (d, J = 13.3 Hz, 1H), 4.58-4.53 (m, 1H), 3.98-3.93 (m 2H), 3.23-3.20 (m, 1H), 2.93-2.92 (m 1H), 2.68-2.62 (m, 1H), 2.24 (s, 3H), 2.16(s,3H),1.87-1.80(m,2H),1.63-1.56 (m,2H),1.41-1.36(m,12H).

LCMS：t=4.43min,601.2(M+). LCMS: t = 4.43 min, 601.2 (M + ).

實施例5：5-氯-2-{2-異丙氧基-5-甲基-4-[1-(2-嗎啉-4-基-乙基)-哌啶-4-基]-苯基}-4-[2-(丙烷-2-磺醯基)-吡啶-3-基]-嘧啶-2,4-二胺的製備 Example 5: 5-Chloro-2-{2-isopropoxy-5-methyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]- Preparation of phenyl}-4-[2-(propane-2-sulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamine

將1-[4-(4-{5-氯-4-[2-(丙烷-2-磺醯基)-吡啶-3-基胺基]-嘧啶-2-基胺基}-5-異丙氧基-2-甲基-苯基)-哌啶-1-基]-乙酮(20mg)溶解在2mL乙醇中，並向其中加入1mL 6N NaOH水溶液，加熱至80℃攪拌過夜，反應液冷卻至室溫，蒸乾溶劑，得到粗產品。將該粗產品溶解在2mL乾燥的DMF中，並向其中加入碳酸鈉(8mg,75μmol)和2-(4-嗎啉)乙基溴氫溴酸鹽(14.58mg,75μmol)，加熱至60℃攪拌過夜。加水稀釋反應液，用乙酸乙酯萃取，合併有機相並用食鹽水洗3~4次，用無水硫酸鈉乾燥有機相，過濾，蒸出溶劑得粗產品，經製備TLC分離得目標化合物5-氯-2-{2-異丙氧基-5-甲基-4-[1-(2-嗎啉-4-基-乙基)-哌啶-4-基]-苯基}-4-[2-(丙烷-2-磺醯基)-吡啶-3-基]-嘧啶-2,4-二胺(12mg,71%)。 1-[4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}-5-iso Propyloxy-2-methyl-phenyl)-piperidin-1-yl]-ethanone (20 mg) was dissolved in 2 mL of ethanol, and 1 mL of 6N aqueous NaOH solution was added thereto, and the mixture was heated to 80 ° C and stirred overnight. After cooling to room temperature, the solvent was evaporated to give a crude material. The crude product was dissolved in 2mL of dry DMF, and thereto is added sodium carbonate (8mg, 75 μ mol) and 2- (4-morpholinyl) ethyl bromide hydrobromide (14.58mg, 75 μ mol), Heat to 60 ° C and stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. EtOAc was evaporated. 2-{2-Isopropoxy-5-methyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-4-[2 -(propane-2-sulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamine (12 mg, 71%).

1H NMR(400MHz,CDCl3)：δ 10.07(s,1H),9.22(d,J=8.6Hz,1H),8.38(dd,J=4.3,1.2Hz,1H),8.18(d,J=3.5Hz, 1H),7.86(s,1H),7.57(s,1H),7.45(dd,J=8.6,4.3Hz,1H),6.96(s,1H),4.77-4.58(m,1H),4.15(t,J=11.6Hz,2H),3.93-3.89(m,3H),3.85-3.66(m,1H),3.58(d,J=6.6Hz,2H),3.37(d,J=11.4Hz,2H),2.86(d,J=3.1Hz,5H),2.68-2.34(m,6H),2.20(s,3H),1.88(br,2H),1.49-1.29(m,12H). 1 H NMR (400MHz, CDCl 3 ): δ 10.07 (s, 1H), 9.22 (d, J = 8.6Hz, 1H), 8.38 (dd, J = 4.3,1.2Hz, 1H), 8.18 (d, J = 3.5 Hz, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.45 (dd, J = 8.6, 4.3 Hz, 1H), 6.96 (s, 1H), 4.77-4.58 (m, 1H), 4.15(t, J = 11.6 Hz, 2H), 3.93-3.89 (m, 3H), 3.85-3.66 (m, 1H), 3.58 (d, J = 6.6 Hz, 2H), 3.37 (d, J = 11.4 Hz) , 2H), 2.86 (d, J = 3.1 Hz, 5H), 2.68-2.34 (m, 6H), 2.20 (s, 3H), 1.88 (br, 2H), 1.49-1.29 (m, 12H).

LCMS：t=3.79min,672.2(M+). LCMS: t = 3.79 min, 672.2 (M + ).

實施例6：5-氯-2-(2-異丙氧基-5-甲基-4-哌啶-4-基-苯基)-4-[2-(丙烷-2-磺醯基)-噻吩-3-基]-嘧啶-2,4-二胺的製備 Example 6: 5-Chloro-2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-4-[2-(propane-2-sulfonyl) Of -thiophen-3-yl]-pyrimidine-2,4-diamine

第一步：3-硝基-2-(丙烷-2-基硫烷基)噻吩的製備 First step: Preparation of 3-nitro-2-(propan-2-ylsulfanyl)thiophene

2-氯-3-硝基噻吩(500mg,3.05mmol)與異丙硫醇(697mg,9.16mmol)混合在N,N-二甲基甲醯胺中，加入碳酸鉀固體(843mg,9.16mmol)，然後在室溫下攪拌2小時。加水和乙酸乙酯分液萃取，合併有機相並用無水硫酸鈉乾燥，過濾，濾液蒸乾得到黃色固體，直接用於下一步反應。 2-Chloro-3-nitrothiophene (500 mg, 3.05 mmol) was mixed with isopropyl mercaptan (697 mg, 9.16 mmol) in N,N-dimethylformamide and added potassium carbonate solid (843 mg, 9.16 mmol) Then, it was stirred at room temperature for 2 hours. The mixture was extracted with water and ethyl acetate. EtOAc was evaporated.

第二步：3-硝基-2-(丙烷-2-基磺醯基)噻吩的製備 Second step: Preparation of 3-nitro-2-(propan-2-ylsulfonyl)thiophene

3-硝基-2-(丙烷-2-基硫烷基)噻吩溶於二氯甲烷中，分批加入間氯過氧化苯甲酸(3.1g,15.2mmol)，加完室溫攪拌 過夜。加入30mL的飽和亞硫酸鈉水溶液，用碳酸鈉調節至pH=9左右，用二氯甲烷提取，有機相硫酸鈉乾燥，過濾，濾液旋乾得白色固體(1.0g,80%)。 3-Nitro-2-(propan-2-ylsulfanyl)thiophene was dissolved in dichloromethane, and m-chloroperoxybenzoic acid (3.1 g, 15.2 mmol) was added portionwise, and stirred at room temperature. overnight. 30 mL of a saturated aqueous solution of sodium sulfite was added, and the mixture was adjusted to pH=9 with sodium carbonate, extracted with dichloromethane, dried over sodium sulfate, filtered, and evaporated to give a white solid (1.0 g, 80%).

第三步：2-(丙烷-2-基磺醯基)噻吩-3-胺的製備 The third step: preparation of 2-(propan-2-ylsulfonyl)thiophen-3-amine

將3-硝基-2-(丙烷-2-基磺醯基)噻吩(200mg,0.85mmol)溶於5mL的甲醇中，加入20mg的鈀/碳(10%)，常壓氫化2小時。TLC(PE：EA=3：1)顯示原料消失，過濾除去鈀/碳，旋乾甲醇得無色油狀物(202mg,100%)。 3-Nitro-2-(propan-2-ylsulfonyl)thiophene (200 mg, 0.85 mmol) was dissolved in 5 mL of methanol, and 20 mg of palladium/carbon (10%) was added and hydrogenated at atmospheric pressure for 2 hours. TLC (PE: EA = 3:1) showed the disappearance of the material, the palladium/carbon was removed by filtration, and methanol was evaporated to give a colorless oil (202 mg, 100%).

第四步：2,5-二氯-N-[2-(丙烷-2-基磺醯基)噻吩-3-基]嘧啶-4-胺的製備 Step 4: Preparation of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)thiophen-3-yl]pyrimidin-4-amine

將2-(丙烷-2-基磺醯基)噻吩-3-胺(870mg,4.2mmol)溶於40mL三氟乙醇中，依次加入2,4,5-三氯嘧啶(3.0g,12.6mmol)和飽和鹽酸二噁烷溶液(4.3mL)，然後在45度下攪拌過夜。反應液直接旋乾經管柱層析得淺黃色固體(220mg,14%)。 2-(Proton-2-ylsulfonyl)thiophen-3-amine (870 mg, 4.2 mmol) was dissolved in 40 mL of trifluoroethanol, followed by 2,4,5-trichloropyrimidine (3.0 g, 12.6 mmol) And a saturated solution of dioxane hydrochloride (4.3 mL), then stirred at 45 ° overnight. The reaction mixture was dried with EtOAc EtOAc.

LC-MS：tR=4.40min,[M+H]+=351.9. LC-MS: t R = 4.40min , [M + H] + = 351.9.

第五步：1-(4-{4-[(5-氯-4-{[2-(丙烷-2-基磺醯基)噻吩-3-基]胺基}嘧啶-2-基)胺基]-2-甲基-5-(丙烷-2- 氧基)苯基}哌啶-1-基)乙酮的製備 Step 5: 1-(4-{4-[(5-chloro-4-{[2-(propan-2-ylsulfonyl)thiophen-3-yl]amino}pyrimidin-2-yl)amine 2-methyl-5-(propane-2- Preparation of oxy)phenyl}piperidin-1-yl)ethanone

將2,5-二氯-N-[2-(丙烷-2-基磺醯基)噻吩-3-基]嘧啶-4-胺(200mg,0.62mmol)溶於N,N-二甲基甲醯胺中，依次加入DIPEA(0.44mL,2.48mmol)和O-苯並三氮唑-N,N,N',N'-四甲基脲四氟硼酸(200mg,0.62mmol)，然後在室溫攪拌過夜，TLC(PE：EA=3：1)顯示原料6消失，往體系中加入20mL的水和20mL的乙酸乙酯，分去水相，有機相硫酸鈉乾燥後直接旋乾用於下一步。 2,5-Dichloro-N-[2-(propan-2-ylsulfonyl)thiophen-3-yl]pyrimidin-4-amine (200 mg, 0.62 mmol) was dissolved in N,N-dimethyl In the guanamine, DIPEA (0.44 mL, 2.48 mmol) and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (200 mg, 0.62 mmol) were added in sequence, and then in the chamber. After stirring overnight, TLC (PE: EA = 3:1) showed that the starting material 6 disappeared. 20 mL of water and 20 mL of ethyl acetate were added to the system, the aqueous phase was separated, and the organic phase was dried over sodium sulfate and then directly dried. step.

LC-MS：tR=4.34min,[M+H]+=451.0. LC-MS: t R = 4.34 min, [M+H] + = 451.0.

第六步：5-氯-N-2-[5-甲基-4-(哌啶-4-乙醯基)-2-(丙烷-2-氧基)苯基]-N-4-[2-(丙烷-2-基磺醯基)噻吩-3-基]嘧啶-2,4-二胺的製備 Step 6: 5-Chloro-N-2-[5-methyl-4-(piperidin-4-ethenyl)-2-(propan-2-oxy)phenyl]-N-4-[ Preparation of 2-(propan-2-ylsulfonyl)thiophen-3-yl]pyrimidine-2,4-diamine

將上一步反應得到的白色固體(130mg,0.28mmol)和1-{4-[4-胺基-2-甲基-5-(丙烷-2-氧基)苯基]哌啶-1-基}-乙酮(110mg,0.42mmol)溶於2mL的二噁烷中，加入對甲基苯磺酸的單水化合物(90mg,0.42mmol)，將體系加熱到150度攪拌過夜。直接旋乾溶劑經管柱層析得到黃色固體(50mg， 28%)。 The white solid obtained in the previous step (130 mg, 0.28 mmol) and 1-{4-[4-amino-2-methyl-5-(propan-2-yloxy)phenyl]piperidin-1-yl }-Ethyl ketone (110 mg, 0.42 mmol) was dissolved in 2 mL of dioxane, and a monohydrate (yield: 90 mg, 0.42 mmol) of p-toluenesulfonic acid was added, and the system was heated to 150 ° C overnight. Direct spin-drying of solvent by column chromatography gave a yellow solid (50 mg, 28%).

LC-MS：tR=4.64min,[M+H]+=606.1。 LC-MS: t R = 4.64min , [M + H] + = 606.1.

第七步：5-氯-N-2-[5-甲基-4-(哌啶-4-基)-2-(丙烷-2-氧基)苯基]-N-4-[2-(丙烷-2-基磺醯基)噻吩-3-基]嘧啶-2,4-二胺的製備 Step 7: 5-Chloro-N-2-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-oxy)phenyl]-N-4-[2- Preparation of (propan-2-ylsulfonyl)thiophen-3-yl]pyrimidine-2,4-diamine

將1-(4-{4-[(5-氯-4-{[2-(丙烷-2-基磺醯基)噻吩-3-基]胺基}嘧啶-2-基)胺基]-2-甲基-5-(丙烷-2-氧基)苯基}哌啶-1-基)乙酮(10mg,0.016mmol)溶於0.1mL的乙醇中，加入30%氫氧化鈉水溶液，然後在100度下攪拌3小時，LC-MS檢測無原料，旋去溶劑，加5mL的水和10mL的乙酸乙酯，有機相乾燥後經管柱層析得化白色固體(1.7mg,17%)。 1-(4-{4-[(5-chloro-4-{[2-(propan-2-ylsulfonyl)thiophen-3-yl]amino}pyrimidin-2-yl)amino]- 2-Methyl-5-(propan-2-yloxy)phenyl}piperidin-1-yl)ethanone (10 mg, 0.016 mmol) was dissolved in 0.1 mL of ethanol, then 30% aqueous sodium hydroxide was added and then After stirring at 100 °C for 3 hours, LC-MS showed no material, and the solvent was evaporated, and 5 mL of water and 10 mL of ethyl acetate were added, and the organic phase was dried and then purified by column chromatography (1.7 mg, 17%).

1H NMR(400MHz,CDCl3)：δ 9.44(s,1H),8.33(d,J=5.4Hz,1H),8.15(s,1H),8.05(s,1H),7.65(d,J=5.4Hz,1H),7.53(s,1H),6.83(s,1H),4.62(dt,J=11.8,6.0Hz,1H),3.69(d,J=11.8Hz,2H),3.34(dt,J=13.7,6.8Hz,1H),3.06(t,J=12.0Hz,2H),2.96(t,J=11.8Hz,1H),2.28(s,3H),2.08-1.93(m,8H),1.48-1.31(m,25H). 1 H NMR (400MHz, CDCl 3 ): δ 9.44 (s, 1H), 8.33 (d, J = 5.4Hz, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 6.83 (s, 1H), 4.62 (dt, J = 11.8, 6.0 Hz, 1H), 3.69 (d, J = 11.8 Hz, 2H), 3.34 (dt, J =13.7, 6.8 Hz, 1H), 3.06 (t, J = 12.0 Hz, 2H), 2.96 (t, J = 11.8 Hz, 1H), 2.28 (s, 3H), 2.08-1.93 (m, 8H), 1.48-1.31 (m, 25H).

LC-MS：tR=3.90min,[M+H]+=564.1. LC-MS: t R = 3.90min , [M + H] + = 564.1.

生物學評價 Biological evaluation

實驗例1：ALK基因融合細胞增殖抑制測試 Experimental Example 1: ALK gene fusion cell proliferation inhibition test

下面的體外試驗可用來測定本發明化合物對於ALK基因融合高表達的人淋巴瘤細胞Karpas 299的增殖抑制活性。 The following in vitro assays can be used to determine the proliferation inhibitory activity of the compounds of the invention against the human lymphoma cell Karpas 299, which is highly expressed by the ALK gene fusion.

以下所述的體外細胞試驗可測定受試化合物的對人淋巴瘤細胞Karpas 299的增殖抑制活性，其活性可用IC50值來表示。此類試驗的一般方案如下：首先選擇人淋巴瘤細胞Karpas 299，以適宜的細胞濃度(例如，6000個細胞/孔中的100μL培養基)接種在96孔培養板上，隨後向各孔加入用培養基稀釋的一系列梯度濃度(一般6到10個濃度)的受試化合物溶液，連續培養72個小時。72小時後，可用CellTiter-Glo® Luminescent Cell Viability Assay kit(購於Promega)。方法測定化合物抑制細胞增殖的活性。IC50值可通過測定一系列不同濃度下，受試化合物對細胞增殖的抑制數值進行計算。 The in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound against human lymphoma cell Karpas 299, and its activity can be expressed by the IC 50 value. General scheme such tests as follows: First, selection of human cell lymphoma Karpas 299, at an appropriate cell concentration (e.g., 100 μ L medium 6000 cells / well) were seeded in 96-well culture plates, then added to each well A series of gradient concentrations (generally 6 to 10 concentrations) of the test compound solution diluted in the medium were continuously cultured for 72 hours. After 72 hours, the CellTiter-Glo® Luminescent Cell Viability Assay kit (available from Promega) was used. The method measures the activity of a compound to inhibit cell proliferation. The IC 50 value can be calculated by measuring the inhibition of cell proliferation by a test compound at a range of different concentrations.

本發明化合物的生化學活性藉由以上試驗進行測定，測得的IC50值見下表。 The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 50 values are shown in the following table.

實驗例2：ALK激酶抑制測試 Experimental Example 2: ALK kinase inhibition test

下面的體外試驗可用來測定本發明化合物對於ALK激酶及產生變異的ALKL1196M激酶抑制活性，其活性可用IC50值來表示。化合物的半數抑制濃度IC50(將一定濃度的酶活性抑制至50%時所需的化合物濃度)是藉由將一定量的激酶與特定的基質及不同濃度的待測化合物混合反應後測定計算出的。本實驗所用的ALK激酶為人源重組蛋白，該酶在含有50mM HEPES(pH7.5)，10mM MgCl2，2M DTT(1000x)的緩衝溶液及30μM ATP的反應體系中與多肽基質以及不同濃度的受試化合物共同進行反應(25℃，45min)，隨後FAM標記抗體對基質進行標記，最後藉由基於微流體晶片技術的Mobility shift技術對ALK激酶活性進行定量測定。 The following in vitro assays may be used to assay the compounds of the present invention to produce and ALK kinase kinase inhibitory activity ALKL1196M variation, which activity can be expressed by IC 50 values. The half-inhibitory concentration IC 50 of the compound (the concentration of the compound required to inhibit a certain concentration of the enzyme activity to 50%) is determined by mixing a certain amount of the kinase with a specific matrix and different concentrations of the test compound. of. The ALK kinase used in this experiment is a human recombinant protein in a reaction system containing 50 mM HEPES (pH 7.5), 10 mM MgCl 2 , 2 M DTT (1000×) buffer solution and 30 μM ATP with a polypeptide matrix and different concentrations. The test compounds were co-reacted (25 ° C, 45 min), followed by FAM-labeled antibodies to label the matrix, and finally the ALK kinase activity was quantified by Mobility shift technology based on microfluidic wafer technology.

本發明化合物的生化學活性藉由以上試驗進行測定，測得的IC50值見下表。 The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 50 values are shown in the following table.

Claims (13)

一種具有通式(I)的化合物或其可藥用鹽： 其中：環A選自5-10員環烷基、5-10員雜環基、5-10員芳基或5-10員雜芳基；R1選自C1-6烷基、鹵素取代的C1-6烷基、C3-6環烷基或4-甲苯基；R2、R3、R4、R5各自獨立的選自氫、鹵素、羥基、氰基、硝基、C1-6烷基、鹵素取代的C1-6烷基、C3-8環烷基、C1-6烷氧基、鹵素取代的C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11；R6、R7、R8各自獨立的選自氫、鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11，其中該C1-8烷基、C3-8環烷基、3-8員雜環基、C5-10芳基或5-10員雜芳基各自獨立視需要進一步被一個或多個選自鹵素、羥基、氰基、硝基、C1-8烷基、C2-8鏈 烯基、C2-8鏈炔基、C3-8環烷基、3-8員雜環基、C5-10芳基、5-10員雜芳基、C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11的取代基所取代；R9、R10、R11選自氫、C1-4烷基；m、n為0、1、2、3、4；L為0、1、2、3、4、5；p為0、1或2。 A compound of the formula (I) or a pharmaceutically acceptable salt thereof: Wherein: Ring A is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclic, 5-10 membered aryl or 5-10 membered heteroaryl; R 1 is selected from C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-6 cycloalkyl or 4-tolyl; R 2 , R 3 , R 4 , R 5 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, C 3-8 cycloalkyl Oxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ; each of R 6 , R 7 , R 8 Independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-8 Heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O R 9 , —C(O)OR 9 , —NR 10 R 11 or —C(O)NR 11 , wherein the C 1-8 alkyl group, the C 3-8 cycloalkyl group, the 3-8 membered heterocyclic group , C 5-10 aryl or 5-10 membered heteroaryl each independently further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, C 1-8 alkyl, C 2-8 olefin group, C 2-8 alkynyl, C 3-8 cycloalkyl Groups, 3-8 membered heterocyclyl, C 5-10 aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S (O) pR 9 Substituted with a substituent of -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ; R 9 , R 10 , R 11 are selected from hydrogen, C 1 -4 alkyl; m, n are 0, 1, 2, 3, 4; L is 0, 1, 2, 3, 4, 5; p is 0, 1 or 2. 如申請專利範圍第1項所述的化合物或其可藥用鹽，其特徵在於：環A與其取代基共同形成的結構選自如下結構： The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the structure formed by the ring A together with the substituent is selected from the following structures: 如申請專利範圍第1項所述的化合物或其可藥用鹽，其特徵在於：環A與其取代基共同形成的結構選自如下結構： 其中，R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、m、 n、L、p如申請專利範圍第1項所定義。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that the structure formed by the ring A together with the substituent is selected from the following structures: Wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, and p are as defined in the first item of the patent application. 如申請專利範圍第1項所述的化合物或其可藥用鹽，其特徵在於：R2、R5各自獨立的選自氫、鹵素、C1-6烷基、鹵素取代的C1-6烷基；R3、R4各自獨立的選自氫、鹵素、羥基、氰基、硝基、C1-6烷基、鹵素取代的C1-6烷基、C3-8環烷基、C1-6烷氧基、鹵素取代的C1-6烷氧基、C3-8環烷基氧基、-S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11；R6、R7、R8、R9、R10、R11、m、n、L、p如申請專利範圍第1項所定義。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, and halogen substituted C 1-6 An alkyl group; R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, C 3-8 cycloalkyloxy, -S(O)pR 9 , -C(O)R 9 , -C(O) OR 9 , -NR 10 R 11 or -C(O)NR 11 ; R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p as in claim 1 definition. 如申請專利範圍第1至4項中任一項所述的化合物或其可藥用鹽，其中該化合物選自： The compound of any one of claims 1 to 4, wherein the compound is selected from the group consisting of: 如申請專利範圍第1項所述的化合物或其可藥用鹽，其特徵在於：其選自式(II)化合物： 其中：R3選自氫、羥基、氰基、硝基、C3-8環烷基、C1-6烷氧基、鹵素取代的C1-6烷氧基、C3-8環烷基氧基、 -S(O)pR9、-C(O)R9、-C(O)OR9、-NR10R11或-C(O)NR11；R2、R4、R5、R6、R7、R8、R9、R10、R11、m、n、L、p如申請專利範圍第1項所定義。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the compound of formula (II): Wherein: R 3 is selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 3-8 cycloalkyl, C 1-6 alkoxy, halogen substituted C 1-6 alkoxy, C 3-8 cycloalkyl Oxy, -S(O)pR 9 , -C(O)R 9 , -C(O)OR 9 , -NR 10 R 11 or -C(O)NR 11 ; R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined in the first item of the patent application. 如申請專利範圍第6項所述的化合物或其可藥用鹽，其特徵在於：R3選自鹵素取代的C1-6烷氧基；R2、R4、R5、R6、R7、R8、R9、R10、R11、m、n、L、p如申請專利範圍第1項所定義。 The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from halogen-substituted C 1-6 alkoxy; R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as defined in item 1 of the scope of the patent application. 如申請專利範圍第7項所述的化合物或其可藥用鹽，其特徵在於：其選自如下化合物： The compound of claim 7, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds: 一種如申請專利範圍第1項所述的具有通式(I)的化合物的製備方法，該製備方法包括如下步驟：式(III)化合物與式(IV)縮合得到式(I)化合物，或者式(III)化合物與式(IV)縮合，然後根據取代基的不同定義或脫保護基轉換成相應的式(I)化合物，其合成路線如下： 其中，環A、R1、R2、R4、R5、R6、R7、R8、R9、R10、R11、m、n、L、p如申請專利範圍第1項所定義。 A process for the preparation of a compound of the formula (I) as described in claim 1, wherein the process comprises the step of: condensing a compound of formula (III) with formula (IV) to give a compound of formula (I), or a formula (III) The compound is condensed with the formula (IV) and then converted to the corresponding compound of the formula (I) according to a different definition of the substituent or a deprotecting group, the synthesis route of which is as follows: Wherein ring A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, n, L, p are as claimed in claim 1 definition. 一種藥物組成物，該藥物組成物含有治療有效劑量的如 申請專利範圍第1至8項中任一項所述的化合物或其可藥用鹽以及可藥用的載體或賦形劑。 A pharmaceutical composition comprising a therapeutically effective dose, such as The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 一種調節蛋白激酶催化活性的方法，其包括將該蛋白激酶與如申請專利範圍第1至8項中任一項所述的化合物或其可藥用鹽，或如申請專利範圍第10項所述的藥物組成物相接觸，該蛋白激酶選自間變性淋巴瘤激酶。 A method for modulating the catalytic activity of a protein kinase, which comprises the protein kinase of the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or as described in claim 10 The drug composition is contacted and the protein kinase is selected from the group consisting of anaplastic lymphoma kinase. 一種如申請專利範圍第1至8項中任一項所述的化合物或其可藥用鹽，或如申請專利範圍第10項所述的藥物組成物在製備治療癌症的藥物的用途。 A use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the preparation of a medicament for treating cancer. 如申請專利範圍第12項所述的用途，其中該癌症為非小細胞肺癌。 The use of claim 12, wherein the cancer is non-small cell lung cancer.
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